Are Epigenetic Factors Implicated in Chronic Widespread Pain?

Burri, Andrea; Marinova, Zoya; Robinson, Mark D.; Kühnel, Brigitte; Waldenberger, Mélanie; Wahl, Simone; Kunze, Sonja; Gieger, Christian; Livshits, Gregory; Williams, Frances

doi:10.1371/journal.pone.0165548

Cited by 22 publications

(19 citation statements)

References 38 publications

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“…The first study was conducted by Burri et al which included a discovery sample consisting of a total of 281 twin individuals from the TwinsUK registry, of which 33 MZ twins discordant for self-reported CWP could be identified. 54 Using the Illumina Infinium HumanMethylation 450 DNA Bead-Chip, 40 potential candidates were identified and carried forward for replication in an independent sample consisting of 729 men and 756 women from a subsample of the KORA S4 survey (an independent population-based cohort from Southern Germany). Of these 40 candidates, three CPGs reached significant p -values in the replication cohort, including MDH2 , tetranectin ( CLEC3B ), and HSPB6 .…”

Section: Resultsmentioning

confidence: 99%

Genetic and epigenetic epidemiology of chronic widespread pain

Kerr¹,

Burri²

2017

JPR

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The etiology underlying chronic widespread pain (CWP) remains largely unknown. An integrative biopsychosocial model seems to yield the most promising explanations for the pathogenesis of the condition, with genetic factors also contributing to disease development and maintenance. Here, we conducted a search of studies investigating the genetic and epigenetic epidemiology of CWP through electronic databases including Web of Science, Medline, PubMed, EMBASE, and Google Scholar. Combinations of keywords including CWP, chronic pain, musculoskeletal pain, genetics, epigenetics, gene, twins, single-nucleotide polymorphism, genotype, and alleles were used. In the end, a total of 15 publications were considered relevant to be included in this review: eight were twin studies on CWP, six were molecular genetic studies on CWP, and one was an epigenetic study on CWP. The findings suggest genetic and unique environmental factors to contribute to CWP. Various candidates such as serotonin-related pathway genes were found to be associated with CWP and somatoform symptoms. However, studies show some limitations and need replication. The presented results for CWP could serve as a template for genetic studies on other chronic pain conditions. Ultimately, a more in-depth understanding of disease mechanisms will help with the development of more effective treatment, inform nosology, and reduce the stigma still lingering on this diagnosis.

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Section: Resultsmentioning

confidence: 99%

Genetic and epigenetic epidemiology of chronic widespread pain

Kerr¹,

Burri²

2017

JPR

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“…Of these genes, TMEM65 (transmembrane protein 65) is the most interesting in the context of fear of pain. TMEM65 is among the most differentially methylated in people with chronic widespread musculoskeletal pain [ 51 ] and also has been implicated in abnormal pain threshold and predisposition to neuropathic pain in rats [ 52 ]. Associations with NEFM and NEFL also are interesting, as they are associated with neuronal functioning, especially for motor neurons [ 53 , 54 ] and may be distally related to pain experience.…”

Section: Discussionmentioning

confidence: 99%

A Preliminary Genome-Wide Association Study of Pain-Related Fear: Implications for Orofacial Pain

Randall

Wright

Chernus

et al. 2017

Pain Research and Management

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Background Acute and chronic orofacial pain can significantly impact overall health and functioning. Associations between fear of pain and the experience of orofacial pain are well-documented, and environmental, behavioral, and cognitive components of fear of pain have been elucidated. Little is known, however, regarding the specific genes contributing to fear of pain. Methods A genome-wide association study (GWAS; N = 990) was performed to identify plausible genes that may predispose individuals to various levels of fear of pain. The total score and three subscales (fear of minor, severe, and medical/dental pain) of the Fear of Pain Questionnaire-9 (FPQ-9) were modeled in a variance components modeling framework to test for genetic association with 8.5 M genetic variants across the genome, while adjusting for sex, age, education, and income. Results Three genetic loci were significantly associated with fear of minor pain (8q24.13, 8p21.2, and 6q26; p < 5 × 10−8 for all) near the genes TMEM65, NEFM, NEFL, AGPAT4, and PARK2. Other suggestive loci were found for the fear of pain total score and each of the FPQ-9 subscales. Conclusions Multiple genes were identified as possible candidates contributing to fear of pain. The findings may have implications for understanding and treating chronic orofacial pain.

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“…In addition, a hypomethylated DNA pattern in FM patients compared to controls was found enriched in genes implicated in stress response and DNA repair/free radical clearance [36]. Another study investigated the DNA methylation status in CWP conditions, identifying differentially methylated CpGs in malate dehydrogenase 2 (MDH2; p-Value 0.017), tetranectin (CLEC3B; p-Value 0.039), and heat shock protein beta-6 (HSPB6; p-Value 0.016) [37]. An epigenome-wide methylation scan through MeDIPseq in whole blood DNA from 1708 monozygotic and dizygotic Caucasian twins highlighted neurological pathways' involvement in CWP, with association signals mapping in or near to IL17A, ADIPOR2, and TNFRSF13B [38].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study

Gerra

Carnevali

Pedersen

et al. 2020

Scandinavian Journal of Pain

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ObjectivesThe present pilot study aims to investigate DNA methylation changes of genes related to fibromyalgia (FM) development and its main comorbid symptoms, including sleep impairment, inflammation, depression and other psychiatric disorders. Epigenetic modifications might trigger or perpetuate complex interplay between pain transduction/transmission, central pain processing and experienced stressors in vulnerable individuals.MethodsWe conducted DNA methylation analysis by targeted bisulfite NGS sequencing testing differential methylation in 112 genomic regions from leukocytes of eight women with FM and their eight healthy sisters as controls.ResultsTests for differentially methylated regions and cytosines brought focus on the GRM2 gene, encoding the metabotropic glutamate receptor2. The slightly increased DNA methylation observed in the GRM2 region of FM patients may confirm the involvement of the glutamate pathway in this pathological condition. Logistic regression highlighted the simultaneous association of methylation levels of depression and inflammation-related genes with FM.ConclusionsAltogether, the results evidence the glutamate pathway involvement in FM and support the idea that a combination of methylated and unmethylated genes could represent a risk factor to FM or its consequence, more than single genes. Further studies on the identified biomarkers could contribute to unravel the causative underlying FM mechanisms, giving reliable directions to research, improving the diagnosis and effective therapies.

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Are Epigenetic Factors Implicated in Chronic Widespread Pain?

Cited by 22 publications

References 38 publications

Genetic and epigenetic epidemiology of chronic widespread pain

Genetic and epigenetic epidemiology of chronic widespread pain

A Preliminary Genome-Wide Association Study of Pain-Related Fear: Implications for Orofacial Pain

DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study

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